Tissue damage, dysfunction, or loss is a feature of a wide variety of medical conditions. Atherosclerosis, in which formation of fatty plaques in blood vessel walls leads to narrowing of the vessels, is one well-known example. Accidents frequently result in damage to tendons, ligaments, and joints. Degenerative diseases such as arthritis represent another source of injury to such tissues. Systemic diseases such as diabetes, cancer, and cirrhosis are yet another cause of organ destruction or dysfunction.
In many of the situations described above, replacement of the damaged tissue or organ is the best or even the only option. Transplantation from human donors (either live or cadaveric) has enjoyed significant success, and procedures such as liver, heart, and kidney transplants are becomingly increasingly common. However, the severe shortage of donors, the complexity of harvesting organs and delivering them to the recipient, and the potential for transmission of infectious agents are significant shortcomings of this approach. In some situations, such as replacement of blood vessels, vessels are removed from one portion of the body and grafted elsewhere to bypass sites of obstruction. However, the number of available vessels is limited, and those available may not be optimal in terms of strength or other parameters.
Use of synthetic materials or tissues derived from animals offer alternatives to the use of human tissues. For example, grafts made of synthetic polymers such as Dacron find use in the replacement of vessels. Mechanical prostheses are widely used to replace damaged heart valves. However, use of synthetic materials has a number of disadvantages. Frequently the material is immunogenic and can serve as a nidus for infection or inflammation. Use of animal tissues also poses problems of immunogenicity as well as the potential to transmit diseases. In addition, harvested animal tissues may be suboptimal in terms of size, shape, or other properties, thus limiting the utility and flexibility of this approach. There is a need for innovative approaches to the problem of replacing damaged or dysfunctional organs and tissues.
Tissue engineering is an evolving field that seeks to develop techniques for culturing replacement tissues and organs in the laboratory (See, for example, Niklason, L. and Langer, R., Advances in tissue engineering of blood vessels and other tissues, Transplant Immunology, 5, 303-306, 1997, which is incorporated herein by reference). The general strategy for producing replacement tissues utilizes mammalian cells that are seeded onto an appropriate substrate for cell culture. The cells can be obtained from the intended recipient (e.g., from a biopsy), in which case they are often expanded in culture before being used to seed the substrate. Cells can also be obtained from other sources (e.g., established cell lines). After seeding, cell growth is generally continued in the laboratory and/or in the patient following implantation of the engineered tissue.
Tissue engineered constructs may be used for a variety of purposes including as prosthetic devices for the repair or replacement of damaged organs or tissues. They may also serve as in vivo delivery systems for proteins or other molecules secreted by the cells of the construct or as drug delivery systems in general. Tissue engineered constructs also find use as in vitro models of tissue function or as models for testing the effects of various treatments or pharmaceuticals.
Tissue engineering technology frequently involves selection of an appropriate culture substrate to sustain and promote tissue growth. In general, these substrates should be three-dimensional and should be processable to form scaffolds of a desired shape for the tissue of interest. Several classes of scaffolds are known. These scaffolds fall into five general categories: (1) non-degradable synthetic polymers; (2) degradable synthetic polymers; (3) non-human collagen gels, which are non-porous; (4) non-human collagen meshes, which are processed to a desired porosity; and (5) human (cadaveric) decellularized collagenous tissue. These different scaffold types are further discussed below.
Non-degradable synthetic polymers, e.g., Dacron and Teflon, may be processed into a variety of fibers and weaves. However, these materials are essentially non-biodegradable and thus represent a nidus for infection or inflammation following implantation into the body. Degradable synthetic polymers, including substances such as polyglycolic acid, polylactic acid, polyanhydrides, etc., may also be processed into various fibers and weaves and have been used extensively as tissue culture scaffolds. These materials may be modified chemically to “tune” their degradation rate and surface characteristics. However, fragments of degradable polyesters can trigger significant and undesirable inflammatory reactions.
Non-human collagen gels, e.g., gels made from bovine collagen and rat-tail collagen are convenient materials to work with in the laboratory, but suffer from significant drawbacks including poor tensile strength, no void volume to allow cell growth and tissue development, and sensitivity to collagenases that weaken the gels over time. Non-human collagen meshes consist of porous meshes made from processed bovine collagen. While the utility of these meshes for tissue engineering applications has been little studied, as with all materials made from bovine proteins they carry the risk of immunologic and/or inflammatory reactions when implanted into a human patient as well as the risk of contamination with agents of prion-based disease.
In summary, none of the tissue culture scaffolds presently available is fully satisfactory from all points of view. Thus there exists a need for improved tissue culture scaffolds for use in tissue engineering.
In general, tissue culture scaffolds represent an intermediate in the production of tissue engineered products. The need for improved tissue culture scaffolds represents one aspect of the broader need for improved tissue engineered products for implantation into a human or animal to replace or supplement diseased, damaged, or absent tissues and/or organs. As in the case of animal tissues, tissue engineered tissues created using cells that are not obtained from the intended recipient may be antigenic. On the other hand, when using cells obtained from the intended recipient, a considerable period of time may be required to produce the tissue engineered tissue or organ, given that only a limited number of cells can be harvested. There is therefore a need for improved methods of producing tissue engineered tissues and organs with minimal antigenicity. There is also a need for more flexible methods of producing tissue engineered tissues and organs, for example, methods that would allow use of cells from the intended recipient while minimizing the time required to produce the engineered tissue or organ.